Inflammation is a normal and vital response mechanism assisting in protecting the body from infection and injury. However abnormal or uncontrolled inflammatory responses can result in the development of acute or chronic inflammatory disorders or conditions. Chronic inflammatory conditions can be debilitating and cause enormous discomfort and pain to sufferers. Moreover inflammatory conditions such as rheumatoid arthritis are increasing in prevalence as populations around the world age.
One fundamental failing of traditional chemically based treatments for inflammatory conditions is that these agents target only the relief of pain associated with the condition rather than addressing the underlying pathophysiology of the condition. Also associated with continued steroid use are significant side effects including stomach ulcers and bleeding. For example, non-steroidal anti-inflammatory drugs (NSAIDs) have been used for many years in anti-inflammatory therapy, however it is well known that NSAIDs produce lesions in the gastrointestinal tract depending on the length of the treatment and on the type of drug. This problem has of particular importance in cases where the therapy must be protracted for a long time, such as in the treatment of chronic inflammatory disorders including rheumatoid arthritis, where long term treatment is needed to keep the inflammatory state and associated pain under control.
Accordingly, there is a growing interest in the development of biological agent-based therapies in an effort to reduce such side effects and slow or reverse the progression of the disease.
Moreover, as most inflammatory and autoimmune diseases are chronic diseases requiring prolonged treatment, injection-based therapies and treatments requiring administration by physicians or other healthcare professionals are not ideal. Thus, the development of alternative therapies and alternative administration approaches is a focus of much research.
One biological agent that has been considered promising for the treatment of some cancers is the cytokine interleukin-2 (IL-2). A recombinant form of interleukin-2, aldesleukin (Proleukin®) has received FDA approval for the treatment of metastatic melanoma and renal cell carcinoma via injection. However to date the widespread and effective employment of IL-2 for therapeutic purposes has been considerably hampered by the significant side effects associated with its administration, due largely to the intravenous or subcutaneous delivery method required and the associated high doses necessary to achieve any therapeutic benefit via injection. Patients receiving systemic IL-2 therapy often experience flu-like symptoms. Hypotension, anaemia, and a decreased platelet count are also associated with the high cumulative doses required for intravenous administration. The most severe toxicities associated with the presently available intravenous or subcutaneous IL-2 administration result from the molecule's ability to increase capillary permeability, which may result in hypotension, ascites, generalized oedema, and pulmonary oedema. Capillary leak syndrome may ultimately lead to severely low blood pressure and reduced blood flow, heart and lung abnormalities, fluid retention, mental changes, kidney abnormalities and/or gastrointestinal abnormalities. These effects may be severe and can result in death.
The need for intravenous or subcutaneous injections of IL-2 also hampers the ability of individuals to self-medicate and manage their own treatment regime. Accordingly there is a need for the development of simple, low cost treatment options that enable sufferers of inflammatory conditions to administer their own medication with convenience and without pain or side effect.
The continued therapeutic application of IL-2 is presently being carefully assessed in light of its significant toxicity and relatively modest clinical response rate. However the present inventor has now surprisingly found, contrary to expectation, that mucosal delivery of IL-2 offers substantial therapeutic benefits over the currently available injectable delivery including the ability to achieve efficacious treatment with much reduced doses compared to those required for presently available systemic delivery. The present invention thereby provides viable new options for the cost-effective, efficacious therapeutic treatment of inflammatory conditions with reduced side effects and allowing patients to administer their own medication.